ERC FUNDED PROJECTS

The brain evolves, develops, and operates in the context of animal movements. As a consequence, fundamental brain functions such as spatial perception and motor control critically depend on the precise knowledge of the ongoing body motion. An accurate internal estimate of self-movement is thought to emerge from sensorimotor integration; nonetheless, which circuits perform this internal estimation, and exactly how motor-sensory coordination is implemented within these circuits are basic questions that remain to be poorly understood. There is growing evidence suggesting that, during locomotion, motor-related and visual signals interact at early stages of visual processing. In mammals, however, it is not clear what the function of this interaction is. Recently, we have shown that a population of Drosophila optic-flow processing neurons —neurons that are sensitive to self-generated visual flow, receives convergent visual and walking-related signals to form a faithful representation of the fly’s walking movements. Leveraging from these results, and combining quantitative analysis of behavior with physiology, optogenetics, and modelling, we propose to investigate circuit mechanisms of self-movement estimation during walking. We will:1) use cell specific manipulations to identify what cells are necessary to generate the motor-related activity in the population of visual neurons, 2) record from the identified neurons and correlate their activity with specific locomotor parameters, and 3) perturb the activity of different cell-types within the identified circuits to test their role in the dynamics of the visual neurons, and on the fly’s walking behavior. These experiments will establish unprecedented causal relationships among neural activity, the formation of an internal representation, and locomotor control. The identified sensorimotor principles will establish a framework that can be tested in other scenarios or animal systems with implications both in health and disease.

1 500 000 €

Start date: 2017-11-01, End date: 2022-10-31

Despite considerable efforts aimed at prevention and treatment, the prevalence of obesity and type 2 diabetes has increased at an alarming rate worldwide over recent decades. Given the urgent need to develop safe and efficient anti-obesity drugs, the scientific community has to intensify efforts to better understand the mechanisms involved in the pathogenesis of obesity. Based on human genome-wide association studies and targeted mouse mutagenesis models, it has recently emerged that the brain controls most aspects of systemic metabolism and that obesity may be a brain disease. I have recently shown that like neurons, astrocytes also respond to circulating nutrients, and they cooperate with neurons to efficiently regulate energy metabolism. So far, the study of brain circuits controlling energy balance has focused on neurons, ignoring the presence and role of astrocytes. Importantly, our studies were the first to describe that exposure to a high-fat, highsugar (HFHS) diet triggers hypothalamic astrogliosis prior to significant body weight gain, indicating a potentially important role in promoting obesity. Overall, my recent findings suggest a novel model in which astrocytes are actively involved in the central nervous system (CNS) control of metabolism, likely including active crosstalk between astrocytes and neurons. To test this hypothetical model, I propose to develop a functional understanding of astroglia-neuronal communication in the CNS control of metabolism focusing on: 1) dissecting the ability of astrocytes to release gliotransmitters to neurons, 2) assessing how astrocytes respond to neuronal activity, and 3) determining if HFHS-induced astrogliosis interrupts this crosstalk and contributes to the development of obesity and type 2 diabetes. These studies aim to uncover the molecular underpinnings of astrocyte-neuron inputs regulating metabolism in health and disease so as to inspire and enable novel therapeutic strategies to fight diabetes and obesity.

1 499 938 €

Start date: 2018-01-01, End date: 2022-12-31

Humans are endowed with a number of advanced cognitive abilities not seen in other species. So what allows the human brain to stand out from the rest in these capabilities? In general, the brains of primates, including humans, have more neurons per unit volume than other mammals. But humans are also in the fortunate position of having the largest of the primate brains, making the number of neurons in the human cerebral cortex greatly expanded. Thus, the difference seems to be a matter of quantity, not quality. My laboratory is interested in understanding how neuron number, and thus brain size, is determined in human brain development. The research proposed here is aimed at taking an evolutionary approach to this question and comparing brain development in an in vitro 3D model system, cerebral organoids. This method, which relies on self-organization from differentiating pluripotent stem cells, recapitulates remarkably well the endogenous developmental program of the human brain. Having previously established the brain organoid approach, and more recently improved upon it with the application of bioengineering, my laboratory is in a unique position to carry out functional studies of human brain development. I propose to use this approach to compare developing human brain tissue to that of other hominid species and tease apart unique features of human neural stem cells and progenitors that allow them to generate more neurons and therefore a greater cerebral cortical size. Furthermore, we will perform transcriptomic and functional screening to identify factors underlying this expansion, followed by careful genetic substitution to test the contributions of putative evolutionary changes. In this way, we will functionally test putative human evolutionary changes in a manner not previously possible.

1 444 911 €

Start date: 2018-07-01, End date: 2023-06-30

Familial forms of neurodegenerative diseases are caused by mutations in a single gene. It is unknown whether distinct mutations in the same gene or in functionally related genes cause disease through similar or disparate mechanisms. Furthermore, the precise molecular mechanisms underlying virtually all neurodegenerative disorders are poorly understood, and effective treatments are typically lacking. This is also the case for Charcot-Marie-Tooth (CMT) peripheral neuropathy caused by mutations in five distinct tRNA synthetase (aaRS) genes. We previously generated Drosophila CMT-aaRS models and used a novel method for cell-type-specific labeling of newly synthesized proteins in vivo to show that impaired protein translation may represent a common pathogenic mechanism. In this proposal, I aim to determine whether translation is also inhibited in CMT-aaRS mouse models, and whether all mutations cause disease through gain-of-toxic-function, or alternatively, whether some mutations act through a dominant-negative mechanism. In addition, I will evaluate whether all CMT-aaRS mutant proteins inhibit translation, and I will test the hypothesis, raised by our unpublished preliminary data shown here, that a defect in the transfer of the (aminoacylated) tRNA from the mutant synthetase to elongation factor eEF1A is the molecular mechanism underlying CMT-aaRS. Finally, I will validate the identified molecular mechanism in CMT-aaRS mouse models, as the most disease-relevant mammalian model. I expect to elucidate whether all CMT-aaRS mutations cause disease through a common molecular mechanism that involves inhibition of translation. This is of key importance from a therapeutic perspective, as a common pathogenic mechanism allows for a unified therapeutic approach. Furthermore, this proposal has the potential to unravel the detailed molecular mechanism underlying CMT-aaRS, what would constitute a breakthrough and a requirement for rational drug design for this incurable disease.

2 000 000 €

Start date: 2018-06-01, End date: 2023-05-31